Nanoparticle-Hydrogel Systems Containing Platensimycin for Local Treatment of Methicillin-Resistant Staphylococcus aureus Infection.

Skin and soft tissue infections require effective and sustained topical administration. Platensimycin (PTM) is a natural drug lead that targets bacterial fatty acid synthases and has a great potential to treat infections caused by methicillin-resistant Staphylococcus aureus (MRSA). To facilitate the use of PTM against local MRSA infections, we prepared polyacrylamide hydrogels containing polyamidoamine (PAMAM)/PTM nanoparticles (NP-gel(PTM)) for the controlled release of PTM. NP-gel(PTM) can continuously inhibit the growth of MRSA and its biofilm formation in simulated drug flow models in vitro. In situ implantation of NP-gel(PTM) could treat MRSA-infected subcutaneous soft tissues without toxicity. For MRSA-infected skin wounds, NP-gel(PTM) not only showed strong anti-MRSA activity but also accelerated more wound healing than the widely used antibiotic mupirocin. Collectively, PTM is expected to be used in this safe and effective NP-gel delivery platform for the treatment of local infections, which might help to alleviate the current antibiotic resistance crisis.

Clinical Pharmacokinetics and Pharmacodynamics of Transarterial Chemoembolization and Targeted Therapies in Hepatocellular Carcinoma.

The management of hepatocellular carcinoma (HCC) is based on a multidisciplinary decision tree. Treatment includes loco-regional therapy, mainly transarterial chemoembolization, for intermediate-stage HCC and systemic therapy with oral tyrosine kinase inhibitors (TKIs) for advanced HCC. Transarterial chemoembolization involves hepatic intra-arterial infusion with either conventional procedure or drug-eluting-beads. The aim of the loco-regional procedure is to deliver treatment as close as possible to the tumor both to embolize the tumor area and to enhance efficacy and minimize systemic toxicity of the anticancer drug. Pharmacokinetic studies applied to transarterial chemoembolization are rare and pharmacodynamic studies even rarer. However, all available studies lead to the same conclusions: use of the transarterial route lowers systemic exposure to the cytotoxic drug and leads to much higher tumor drug concentrations than does a similar dose via the intravenous route. However, reproducibility of the procedure remains a major problem, and no consensus exists regarding the choice of anticancer drug and its dosage. Systemic therapy with TKIs is based on sorafenib and lenvatinib as first-line treatment and regorafenib and cabozantinib as second-line treatment. Clinical use of TKIs is challenging because of their complex pharmacokinetics, with high liver metabolism yielding both active metabolites and their common toxicities. Changes in liver function over time with the progression of HCC adds further complexity to the use of TKIs. The challenges posed by TKIs and the HCC disease process means monitoring of TKIs is required to improve clinical management. To date, only partial data supporting sorafenib monitoring is available. Results from further pharmacokinetic/pharmacodynamic studies of these four TKIs are eagerly awaited and are expected to permit such monitoring and the development of consensus guidelines.

Traitement médical des carcinomes basocellulaires avancés: Medical treatment of advanced basal cell carcinoma.

Until recently, advanced BCC were only accessible to a highly morbid surgery not necessarily proving to be carcinologic, and leaving terrible dysmorphic sequelae hard to accept by the patient. Another possibility, the only one in case of metastatic BCC, was chemotherapy which efficacy has never been proven in a clinical trial. Radiotherapy is most often not accessible because of previous radiotherapy or because of the localization or the extension of the lesion. The discovery of the importance of the sonic hedgehog pathway in the physiopathology of BCC has opened a new strategy with the development of targeted anti SMO drugs inactivating the pathway. Two molecules have become available following Phase I and II studies: vismodegib (Erivedge®) the first in class indicated for locally advanced and metastatic BCC and sonidegib (Odomzo®) indicated only for locally advanced BCC. The pharmacokinetic profiles of sonidegib and vismodegib showed several differences. No head to head comparative studies are available between these two drugs. Their pivotal phase II studies had similar study designs and endpoints. The objective response rate (ORR) by central review for vismodegib was 47.6% (95% CI 35.5-60.6) at 21 months follow-up. The ORR for sonidegib according to central review at 18 months follow-up is 56.1% (95% CI 43.3-68.3). Although both treatments share a similar adverse event profile with possible numerically differences in incidence, most patients will discontinue hedgehog inhibitors treatment in the long term because of side effects. Some resistant cases to these drugs have been described but are rather rare. In case of resistance or bad tolerability to the drug future hopes rely on immunotherapy currently under investigation. © 2018. Published by Elsevier Masson SAS. All rights reserved. Cet article fait partie du numéro supplément Prise en charge des carcinomes basocellulaires difficiles à traiter réalisé avec le soutien institutionnel de Sun Pharma.

Ombitasvir: a potent pan-genotypic inhibitor of NS5A for the treatment of hepatitis C virus infection.

Hepatitis C virus (HCV) chronically infects about 150,000,000 people worldwide and is a relevant cause of liver cirrhosis, hepatocellular carcinoma and death. Antiviral treatment is rapidly moving from interferon (IFN)-based therapy to IFN-free approaches. This review focuses on the mechanism of action, pharmacokinetics, efficacy, tolerability, safety and resistance of ombitasvir, which is an inhibitor of the HCV nonstructural protein 5A. The pharmacokinetics of ombitasvir enables its once daily administration. In vivo, in combinations with other oral direct acting antivirals, ombitasvir achieves very high rates of sustained virological response (about 95%) in patients with HCV genotype 1 infection with a good tolerability. Resistance profiling revealed a low barrier to resistance when given as monotherapy. However, coadministration of ombitasvir and other antivirals enhances its barrier to resistance. In conclusion, ombitasvir is a good drug to be used in IFN-free combinations for the treatment of chronic hepatitis C.

Pharmacokinetic evaluation of cabozantinib for the treatment of thyroid cancer.

INTRODUCTION: Conventional treatment modalities for thyroid cancer lead to complete remission in only one-third of patients with distant metastases. On the other hand, medullary thyroid cancer (MTC) and anaplastic thyroid cancer (ATC), although rare, are responsible for a significant percentage of thyroid cancer-related deaths. New treatments are needed to treat such patients. AREAS COVERED: The aim of this review is to provide the latest information on cabozantinib (CBZ), a new tyrosine kinase inhibitor (TKI) that is currently used mainly as a treatment of MTC. The authors collated data that were retrieved from a PubMed literature search. EXPERT OPINION: CBZ targets multiple cell-signaling pathways involved in the molecular pathogenesis of thyroid cancer. These are namely VEGF receptor-2, hepatocyte growth factor receptor and rearranged during transfection receptor. Furthermore, it is a drug which may be used in cases where conventional therapies (mainly for MTC) are proved ineffective or have shown poor results with a good outcome. CBZ may also be administered alone or in combination with other drugs of the same family.

Case studies addressing human pharmacokinetic uncertainty using a combination of pharmacokinetic simulation and alternative first in human paradigms.

PF-184298 ((S)-2,3-dichloro-N-isobutyl-N-pyrrolidin-3-ylbenzamide) and PF-4776548 ((3-(4-fluoro-2-methoxy-benzyl)-7-hydroxy-8,9-dihydro-3H,7H-pyrrolo[2,3-c][1,7]naphthyridin-6-one)) are novel compounds which were selected to progress to human studies. Discordant human pharmacokinetic predictions arose from pre-clinical in vivo studies in rat and dog, and from human in vitro studies, resulting in a clearance prediction range of 3 to >20 mL min⁻¹ kg⁻¹ for PF-184298, and 5 to >20 mL min⁻¹ kg⁻¹ for PF-4776548. A package of work to investigate the discordance for PF-184298 is described. Although ultimately complementary to the human pharmacokinetic data in characterising the disposition of PF-184298 in humans, these data did not provide any further confidence in pharmacokinetic prediction. A fit for purpose human pharmacokinetic study was conducted for each compound, with an oral pharmacologically active dose for PF-184298, and an intravenous and oral microdose for PF-4776548. This provided a relatively low cost, clear decision making approach, resulting in the termination of PF-4776548 and further progression of PF-184298. A retrospective analysis of the data showed that, if the tools had been available at the time, the pharmacokinetics of PF-184298 in human could have been predicted from a population based simulation tool in combination with physicochemical properties and in vitro human intrinsic clearance.

Interplay of dissolution, solubility, and nonsink permeation determines the oral absorption of the Hedgehog pathway inhibitor GDC-0449 in dogs: an investigation using preclinical studies and physiologically based pharmacokinetic modeling.

Factors determining the pharmacokinetics of 2-chloro-N-(4-chloro-3-(pyridine-2-yl)phenyl)-4-(methylsulfonyl)benzamide (GDC-0449) were investigated using preclinical studies and physiologically based pharmacokinetic (PBPK) modeling. Multiple-dose studies where dogs were given twice-daily oral doses of either 7.5 or 25 mg/kg GDC-0449 showed less than dose-proportional increases in exposure on day 1. At steady state, exposures were comparable between the two dose groups. Oral administration of activated charcoal to dogs receiving oral or intravenous GDC-0449 (25 mg) showed a more rapid decrease in plasma concentrations, suggesting that the concentration gradient driving intestinal membrane permeation was reversible. The biliary clearance of GDC-0449 in dogs was low (0.04 ml/min/kg) and did not account for the majority of the estimated systemic clearance (approximately 19% of systemic clearance). Likewise, in vitro studies using sandwich-cultured human hepatocytes showed negligible biliary excretion. The effect of particle size on oral absorption was shown in a single-dose study where 150 mg of GDC-0449 of two particle sizes was administered. An oral PBPK model was used to investigate mechanisms determining the oral pharmacokinetics of GDC-0449. The overall oral absorption of GDC-0449 appears to depend on the interplay between the dissolution and intestinal membrane permeation processes. A unique feature of GDC-0449 distinguishing it from other Biopharmaceutical Classification System II compounds was that incorporation of the effects of solubility rate-limited absorption and nonsink permeation on the intestinal membrane permeation process was necessary to describe its pharmacokinetic behavior.

Metabolism, pharmacokinetics and excretion of the GABA(A) receptor partial agonist [(14)C]CP-409,092 in rats.

The metabolism and excretion of a GABA(A) partial agonist developed for the treatment of anxiety, CP-409,092; 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (4-methylaminomethyl-phenyl)-amide, were studied in rats following intravenous and oral administration of a single doses of [(14)C]CP-409,092. The pharmacokinetics of CP-409,092 following single intravenous and oral doses of 4 and 15 mg kg(-1), respectively, were characterized by high clearance of 169 + or - 18 ml min(-1) kg(-1), a volume of distribution of 8.99 + or - 1.46 l kg(-1), and an oral bioavailability of 2.9% + or - 3%. Following oral administration of 100 mg kg(-1) [(14)C]CP-409,092, the total recovery was 89.1% + or - 3.2% for male rats and 89.3% + or - 0.58% for female rats. Approximately 87% of the radioactivity recovered in urine and faeces were excreted in the first 48 h. A substantial portion of the radioactivity was measured in the faeces as unchanged drug, suggesting poor absorption and/or biliary excretion. There were no significant gender-related quantitative/qualitative differences in the excretion of metabolites in urine or faeces. The major metabolic pathways of CP-409,092 were hydroxylation(s) at the oxo-tetrahydro-indole moiety and oxidative deamination to form an aldehyde intermediate and subsequent oxidation to form the benzoic acid. The minor metabolic pathways included N-demethylation and subsequent N-acetylation and oxidation. The present work demonstrates that oxidative deamination at the benzylic amine of CP-409,092 and subsequent oxidation to form the acid metabolite seem to play an important role in the metabolism of the drug, and they contribute to its oral clearance and low exposure.

Preclinical assessment of the absorption, distribution, metabolism and excretion of GDC-0449 (2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide), an orally bioavailable systemic Hedgehog signalling pathway inhibitor.

GDC-0449 (2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide) is a potent, selective Hedgehog (Hh) signalling pathway inhibitor being developed for the treatment of various cancers. The in vivo clearance of GDC-0449 was estimated to be 23.0, 4.65, 0.338, and 19.3 ml min(-1) kg(-1) in mouse, rat, dog and monkeys, respectively. The volume of distribution ranged from 0.490 in rats to 1.68 l kg(-1) in mice. Oral bioavailability ranged from 13% in monkeys to 53% in dogs. Predicted human clearance using allometry was 0.096-0.649 ml min(-1) kg(-1) and the predicted volume of distribution was 0.766 l kg(-1). Protein binding was extensive with an unbound fraction less than or equal to 6%, and the blood-to-plasma partition ratio ranged from 0.6 to 0.8 in all species tested. GDC-0449 was metabolically stable in mouse, rat, dog and human hepatocytes and had a more rapid turnover in monkey hepatocytes. Proposed metabolites from exploratory metabolite identification in vitro (rat, dog and human liver microsomes) and in vivo (dog and rat urine) include three primary oxidative metabolites (M1-M3) and three sequential glucuronides (M4-M6). Oxidative metabolites identified in microsomes M1 and M3 were formed primarily by P4503A4/5 (M1) and P4502C9 (M3). GDC-0449 was not a potent inhibitor of P4501A2, P4502B6, P4502D6, and P4503A4/5 with IC50 estimates greater than 20 microM. K(i)'s estimated for P4502C8, P4502C9 and P4502C19 and were 6.0, 5.4 and 24 microM, respectively. An evaluation with Simcyp suggests that GDC-0449 has a low potential of inhibiting P4502C8 and P4502C9. Furthermore, GDC-0449 (15 microM) was not a potent P-glycoprotein/ABCB1 inhibitor in MDR1-MDCK cells. Overall, GDC-0449 has an attractive preclinical profile and is currently in Phase II clinical trials.

A small-molecule therapeutic lead for Huntington's disease: preclinical pharmacology and efficacy of C2-8 in the R6/2 transgenic mouse.

Huntington's disease (HD) is a progressive neurodegenerative disease caused by a glutamine expansion within huntingtin protein. The exact pathological mechanisms determining disease onset and progression remain unclear. However, aggregates of insoluble mutant huntingtin (mhtt), a hallmark of HD, are readily detected within neurons in HD brain. Although aggregated polyglutamines may not be inherently toxic, they constitute a biomarker for mutant huntingtin useful for developing therapeutics. We previously reported that the small molecule, C2-8, inhibits polyglutamine aggregation in cell culture and brain slices and rescues degeneration of photoreceptors in a Drosophila model of HD. In this study, we assessed the therapeutic potential of C2-8 in the R6/2 mouse model of HD, which has been used to provide proof-of-concept data in considering whether to advance therapies to human HD. We show that, at nontoxic doses, C2-8 penetrates the blood-brain barrier and is present in brain at a high concentration. C2-8-treated mice showed improved motor performance and reduced neuronal atrophy and had smaller huntingtin aggregates. There have been no prior drug-like, non-toxic, brain-penetrable aggregation inhibitors to arise from cell-based high-throughput screens for reducing huntingtin aggregation that is efficacious in preclinical in vivo models. C2-8 provides an essential tool to help elucidate mechanisms of neurodegeneration in HD and a therapeutic lead for further optimization and development.

Synthesis and evaluation of a bromine-76-labeled PPARgamma antagonist 2-bromo-5-nitro-N-phenylbenzamide.

Peroxisome proliferator activated-receptor gamma (PPARgamma) binds to peroxisome receptor response elements with its heterodimeric partner, retinoid X receptor, and regulates downstream gene expression. PPARgamma transcriptionally modulates fat metabolism, and receptor agonists have been developed to treat type II diabetes. PPARgamma is also overexpressed in some tumor cell lines and primary tumors, including breast and prostate tumors. Two PPARgamma antagonists, 2-chloro-5-nitro-N-phenylbenzamide (GW9662) and 2-chloro-5-nitro-N-pyridin-4-yl-benzamide (T0070907), represent good lead compounds for radiotracer development. In the current study, four additional halogen substituted analogs were synthesized and evaluated in a whole cell screening assay for PPARgamma binding activity. Two bromine-containing analogs having EC50 values <5 nM were chosen for bromine-76 radiolabeling. Bromine-76-labeled 2-bromo-5-nitro-N-phenyl-benzamide was selected for subsequent in vitro and in vivo studies due to its superior radiolabeling yield (approximately 70%) and the well-characterized pharmacological properties of its analog GW9662. An in vitro stability study showed that 40% of the compound remained intact in plasma and about 25% in whole blood after 30 min. Biodistribution studies in MDA-MB-435 human breast tumor-bearing nude mice were carried out at 5 min, 30 min, 2 h and 24 h post injection of the radiotracer. Although in vivo metabolite studies demonstrated rapid compound degradation, at least 10% of the parent compound was delivered to the tumor. We are currently exploring second generation analogs of these lead compounds for the development of radiolabeled antagonists of the PPARgamma receptor.

Absorption of dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides after oral application of Echinacea purpurea tincture.

Alkamides are suspected to contribute to the activity of Echinacea preparations. In preliminary experiments a quantification method for dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides in human blood has been developed by which it was possible to detect dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides in human blood after oral application of Echinacea purpurea mother tincture.

Design, synthesis, and pharmacological evaluation of ultrashort- to long-acting opioid analgetics.

In an effort to discover a potent ultrashort-acting mu opioid analgetic that is capable of metabolizing to an inactive species independent of hepatic function, several classes of 4-anilidopiperidine analgetics were synthesized and evaluated. One series of compounds displayed potent mu opioid agonist activity with a high degree of analgesic efficacy and an ultrashort to long duration of action. These analgetics, 4-(methoxycarbonyl)-4-[(1-oxopropyl)phenylamino]-1-piperidinepropanoi c acid alkyl esters, were evaluated in vitro in the guinea pig ileum for mu opioid activity, in vivo in the rat tail withdrawal assay for analgesic efficacy and duration of action, and in vitro in human whole blood for their ability to be metabolized in blood. Compounds in this series were all shown to be potent mu agonists in vitro, but depending upon the alkyl ester substitution the potency and duration of action in vivo varied substantially. The discrepancies between the in vitro and in vivo activities and variations in duration of action are probably due to different rates of ester hydrolysis by blood esterase(s). The SAR with respect to analgesic activity and duration of action as a function of the various esters synthesized is discussed. It was also demonstrated that the duration of action for the ultrashort-acting analgetic, 8, does not change upon prolonged infusion or administration of multiple bolus injections.

Genetically determined stereoselective excretion of encainide in humans and electrophysiologic effects of its enantiomers in canine cardiac Purkinje fibers.

Encainide metabolism is mediated by the polymorphically distributed cytochrome P450IID6, which displays stereoselectivity for some substrates. In this study we found that urinary recovery during steady-state encainide in three poor metabolizers was high (49% to 80%), consisted mainly of unchanged encainide, was nonstereoselective (+/- ratio, 0.985 to 1.049), and was unchanged by quinidine, a potent inhibitor of P450IID6. In contrast, in seven extensive metabolizers the +/- urinary ratios were 1.20 +/- 0.06 for encainide and 0.81 +/- 0.06 (both p less than 0.01) for the cytochrome P450IID6 products O-desmethylencainide plus 3-methoxy-O-desmethylencainide; with quinidine the total percentage recovery rose from 4% +/- 4% to 37% +/- 9% because of increased recovery of unchanged encainide and became non-stereoselective (+/- ratio, 0.84 +/- 0.08 [encainide alone] versus 0.97 +/- 0.05 [encainide plus quinidine]). In vitro, encainide enantiomers depressed the maximum rate of metabolism with similar frequency and concentration dependence. We conclude that (-)-encainide undergoes preferential metabolism by cytochrome P450IID6; however, this genetically determined stereoselective disposition is unlikely to play a major role in mediating the clinical actions of encainide.

Casodex: preclinical studies.

Antiandrogens are effective drugs in the treatment of advanced prostatic cancer. The main problems associated with their use are their short half-lives, leading to fluctuating serum levels, and their non-selectivity, which leads to increases in serum LH and testosterone through centrally-mediated actions. Casodex is a pure, potent antiandrogen which, in pre-clinical studies, has been shown to have a long half-life and a high degree of peripheral selectivity. Casodex is as effective as surgical castration or medical castration with Zoladex in inhibiting the growth of a transplantable Dunning prostate tumor in rats. These properties suggest that Casodex, given once daily, would be an effective and well-tolerated monotherapy for advanced prostatic cancer.